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Mechanisms of Ozone-Induced Alterations in Efferocytosis and Phagocytosis

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03646877
Recruitment Status : Suspended (COVID 19)
First Posted : August 24, 2018
Last Update Posted : May 14, 2020
Sponsor:
Collaborators:
National Institutes of Health (NIH)
East Carolina University
Information provided by (Responsible Party):
Robert Tighe, MD, Duke University

Brief Summary:

The purpose of this research study to understand how environmental and genetic factors may be involved in lung function. Healthy Study participants will undergo a 1-day screening that includes a blood draw and breathing testing, return for a two-day series of testing to include blood draw, and brief breathing test before and after an inhaled challenge with either filtered air (FA) or ozone (O3). Participants return the next day for a brief breathing test, a blood draw and a procedure called bronchoscopy performed under conscious sedation to evaluate the lung after the challenge.

Participants then return 18 - 20 days later to repeat the two-day series of testing to be challenged with the exposure not received on the first series, (FA or O3). Each visit will take about 3 - 3.5 hours. Follow-up phone calls from the study team will occur at 24 hours after each 2-day test series. Total study duration is about one to one-and a half months.


Condition or disease Intervention/treatment Phase
Healthy Drug: Ozone Other: Filtered Air Phase 1

Detailed Description:
In brief, at V1 subjects will be assessed for baseline spirometry and venous blood analysis prior to exposure. The venous blood will be used to obtain PMNs for apoptosis assays, and serum for CFH and sCD163 levels. Additionally, this will be used to measure cytokines and growth factors. At each visit, if the subject is female, there will be a urine pregnancy test performed. Following this initial assessment, subjects will be challenged with FA or O3 and then spirometry will be performed, and venous blood will be obtained immediately following the exposure (V2). The subjects will then return 20 hours ±4h later for follow up studies (V3). There will be spirometry, a venous blood draw and urine pregnancy testing (if female) followed by bronchoscopy. At bronchoscopy, vital signs will be determined, including O2 sat. Patient then undergo an 18-20 day washout period before they are brought back in for V4 for the alternate challenge. This will follow the same protocol as outline above in the initial exposure and use the same series of analysis as the first set of visits. Therefore, we will fully characterize the biological response to ozone and filtered air in these same subjects.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 70 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single (Participant)
Primary Purpose: Other
Official Title: Mechanisms of Ozone-Induced Alterations in Efferocytosis and Phagocytosis
Actual Study Start Date : February 19, 2019
Estimated Primary Completion Date : January 31, 2024
Estimated Study Completion Date : January 31, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Ozone

Arm Intervention/treatment
Experimental: Ozone (O3)
The O3 level during the exposures will be 200 ppb, which has previously been used in human exposure studies without short or long term, untoward side effects (and comparable to peak levels attained during the summer in the Raleigh-Durham area of North Carolina) (REF - Bromberg review).
Drug: Ozone
Subjects will perform alternating 15 minutes rest with 15 minutes treadmill walk exercise periods for 135 minutes in while breathing Ozone (O3).
Other Name: O3

Placebo Comparator: Filtered Air (FA)
Control will be treadmill walk with filtered room air in chamber.
Other: Filtered Air
Subjects will perform alternating 15 minutes rest with 15 minutes treadmill walk exercise periods for 135 minutes in while breathing filtered air.




Primary Outcome Measures :
  1. change in ozone induced efferocytosis of lung macrophages (ability to clear dead or dying cells) [ Time Frame: Baseline, 21 days ]
    Efferocytosis is defined by determining the number of apoptotic PMNs phagocytized by alveolar macrophages (BAL cytospins) versus the total number of macrophages ('efferocytic index')

  2. Change in ozone induced phagocytosis of lung macrophages (ability to clear debris or bacteria) [ Time Frame: Baseline, 21 days ]
    Bronchoalveolar macrophages are incubated with pHrodo™ dye-labeled particles. Macrophage phagocytosis will be defined by determining the number of macrophages that contain fluorescent particles versus the total macrophages Cell free hemoglobin and soluble CD163 - both are measured by commercial ELISA kit


Secondary Outcome Measures :
  1. Change in ozone induced increase in cell free hemoglobin in bronchoalveolar lavage fluid and serum [ Time Frame: Baseline, 21 days ]
    Measured by enzyme-linked immunosorbent assay (ELISA)

  2. Change in ozone induced increase in soluble CD163 in bronchoalveolar lavage fluid and serum [ Time Frame: Baseline, 21 days ]
    Measured by enzyme-linked immunosorbent assay (ELISA)



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Ages Eligible for Study:   18 Years to 35 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria

• Individuals between 18-35 yrs. of age (No subject will be excluded from the study on the basis of gender or ethnicity)

Exclusion Criteria

  • Current smokers of tobacco products including e-cigarettes or those with previous smoking history within the prior 5 years
  • Pregnant women and women who are presently lactating.
  • Subjects that have received antibiotic administration or an upper respiratory infection within the previous 4 weeks
  • College and graduate students or employees who are under direct supervision by any of the investigators in this protocol
  • Alcohol or illicit substance abuse
  • Chronic cardio/pulmonary respiratory disorders or other medical conditions as determined by the investigator
  • Increased airway hyperresponsiveness at baseline as measured by a positive methacholine challenge response (methacholine PC20 FEV1 < 8 mg/ml)
  • Subjects will be requested to refrain from antihistamines, nonsteroidal anti-inflammatory agents, antioxidants (e.g. beta-carotene, selenium, and lutein) and supplemental vitamins (e.g. C and E), for 1 week prior to, and during testing.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03646877


Locations
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United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27710
Sponsors and Collaborators
Robert Tighe, MD
National Institutes of Health (NIH)
East Carolina University
Investigators
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Principal Investigator: Robert Tighe, MD Duke University
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Responsible Party: Robert Tighe, MD, Assistant Professor of Medicine, Duke University
ClinicalTrials.gov Identifier: NCT03646877    
Other Study ID Numbers: PRO00100375
First Posted: August 24, 2018    Key Record Dates
Last Update Posted: May 14, 2020
Last Verified: May 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No